title: Transcriptional regulation of the beta-synuclein 5'-promoter metal response element by metal transcription factor-1.
abstract: The progression of many human neurodegenerative disorders is associated with an accumulation of alpha-synuclein. Alpha-synuclein belongs to the homologous synuclein family, which includes beta-synuclein. It has been proposed that beta-synuclein may be a natural regulator of alpha-synuclein. Therefore controlling beta-synuclein expression may control the accumulation of alpha-synuclein and ultimately prevent disease progression. The regulation of synucleins is poorly understood. We investigated the transcriptional regulation of beta-synuclein, with the aim of identifying molecules that differentially control beta-synuclein expression levels. To investigate transcriptional regulation of beta-synuclein, we used reporter gene assays and bioinformatics. We identified a region -1.1/-0.6 kb upstream of the beta-synuclein translational start site to be a key regulatory region of beta-synuclein 5'-promoter activity in human dopaminergic cells (SH-SY5Y). Within this key promoter region we identified a metal response element pertaining to a putative Metal Transcription Factor-1 (MTF-1) binding site. We demonstrated that MTF-1 binds to this 5'-promoter region using EMSA analysis. Moreover, we showed that MTF-1 differentially regulates beta-synuclein promoter binding site, as well as beta-synuclein mRNA and protein expression. This effect of MTF-1 on expression was found to be specific to beta-synuclein when compared to alpha-synuclein. Understanding the regulation of synucleins and how they interact may point to molecular targets that could be manipulated for therapeutic benefit. In this study we showed that MTF-1 differentially controls the expression of beta-synuclein when compared to its homolog alpha-synuclein. This could potentially provide a novel targets or pathways for therapeutic intervention and/or treatment of synucleinopathies.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: McHugh
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Wright
authors.forename: David R
authors.initials: DR
authors.lastname: Brown
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008670:Metals / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D020218:Response Elements / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D051846:beta-Synuclein / Q000235:genetics* / Q000378:metabolism; D000097809:Transcription Factor MTF-1
chemical_list: D020121:5' Untranslated Regions; D004268:DNA-Binding Proteins; D008670:Metals; D014157:Transcription Factors; D051846:beta-Synuclein; D000097809:Transcription Factor MTF-1